8-Substituted-6,7,8,9-tetrahydropyrimido [1,2-a] pyrimidin-4-one derivatives.

ABSTRACT

The invention relates to substituted-pyrimidone derivatives represented by formula (I) or a salt thereof: 
                         
wherein X, Y, R1, R2, R3, R4, R5, n, p and q are as defined herein. The invention relates also to a medicament comprising the said derivative or a salt thereof as an active ingredient which is used for preventive and/or therapeutic treatment of a neurodegenerative disease caused by abnormal activity of GSK3β, such as Alzheimer&#39;s disease.

This application is a continuation of International application No.PCT/EP2004/004014, filed Mar. 19, 2004 which is incorporated herein byreference in its entirety; which claims the benefit of priority ofEuropean Patent Application No. 03290727.1, filed Mar. 21, 2003.

TECHNICAL FIELD

The present invention relates to compounds that are useful as an activeingredient of a medicament for preventive and/or therapeutic treatmentof neurodegenerative diseases caused by abnormal activity of GSK3β.

BACKGROUND ART

GSK3β (glycogen synthase kinase 3β) is a proline directed serine,threonine kinase that plays an important role in the control ofmetabolism, differentiation and survival. It was initially identified asan enzyme able to phosphorylate and hence inhibit glycogen synthase. Itwas later recognized that GSK3β was identical to tau protein kinase 1(TPK1), an enzyme that phosphorylates tau protein in epitopes that arealso found to be hyperphosphorylated in Alzheimer's disease and inseveral taupathies. Interestingly, protein kinase B (AKT)phosphorylation of GSK3β results in a loss of its kinase activity, andit has been hypothesized that this inhibition may mediate some of theeffects of neurotrophic factors. Moreover, phosphorylation by GSK3β ofβ-catenin, a protein involved in cell survival, results in itsdegradation by an ubiquitinilation dependent proteasome pathway.

Thus, it appears that inhibition of GSK3β activity may result inneurotrophic activity. Indeed there is evidence that lithium, anuncompetitive inhibitor of GSK3β, enhances neuritogenesis in some modelsand also increases neuronal survival, through the induction of survivalfactors such as Bcl-2 and the inhibition of the expression ofproapoptotic factors such as P53 and Bax.

Recent studies have demonstrated that β-amyloid increases the GSK3βactivity and tau protein phosphorylation. Moreover, thishyperphosphorylation as well as the neurotoxic effects of β-amyloid areblocked by lithium chloride and by a GSK3β antisense mRNA. Theseobservations strongly suggest that GSK3β may be the link between the twomajor pathological processes in Alzheimer's disease: abnormal APP(Amyloid Precursor Protein) processing and tau proteinhyperphosphorylation.

Although tau hyperphosphorylation results in a destabilization of theneuronal cytoskeleton, the pathological consequences of abnormal GSK3βactivity are, most likely, not only due to a pathologicalphosphorylation of tau protein because, as mentioned above, an excessiveactivity of this kinase may affect survival through the modulation ofthe expression of apoptotic and antiapoptotic factors. Moreover, it hasbeen shown that β-amyloid-induced increase in GSK3β activity results inthe phosphorylation and, hence the inhibition of pyruvate dehydrogenase,a pivotal enzyme in energy production and acetylcholine synthesis.

Altogether these experimental observations indicate that GSK3β may findapplication in the treatment of the neuropathological consequences andthe cognitive and attention deficits associated with Alzheimer'sdisease, as well as other acute and chronic neurodegenerative diseases.These include, in a non-limiting manner, Parkinson's disease, taupathies(e.g. frontotemporoparietal dementia, corticobasal degeneration, Pick'sdisease, progressive supranuclear palsy) and other dementia includingvascular dementia; acute stroke and others traumatic injuries;cerebrovascular accidents (e.g. age related macular degeneration); brainand spinal cord trauma; peripheral neuropathies; retinopathies andglaucoma.

In addition GSK3β, may find application in the treatment of otherdiseases such as: non-insulin dependent diabetes (such as diabetes typeII) and obesity; manic depressive illness; schizophrenia; alopecia;cancers such as breast cancer, non-small cell lung carcinoma, thyroidcancer, T or B-cell leukemia and several virus-induced tumors.

DISCLOSURE OF THE INVENTION

An object of the present invention is to provide compounds useful as anactive ingredient of a medicament for preventive and/or therapeutictreatment of a disease caused by abnormal GSK3β activity, moreparticularly of neurodegenerative diseases. More specifically, theobject is to provide novel compounds useful as an active ingredient of amedicament that enables prevention and/or treatment of neurodegenerativediseases such as Alzheimer's disease.

Thus, the inventors of the present invention have identified compoundspossessing inhibitory activity against GSK3β. As a result, they foundthat compounds represented by the following formula (I) had the desiredactivity and were useful as an active ingredient of a medicament forpreventive and/or therapeutic treatment of the aforementioned diseases.The present invention thus provides substituted-pyrimidone derivativesrepresented by formula (I) or salts thereof, solvates thereof orhydrates thereof:

wherein:

-   X represents two hydrogen atoms, a sulfur atom, an oxygen atom or a    C₁₋₂ alkyl group and a hydrogen atom;-   Y represents a bond, a carbonyl group, a methylene group optionally    substituted by one or two groups chosen from a C₁₋₆ alkyl group, a    hydroxyl group, a C₁₋₄ alkoxy group, a C₁₋₂ perhalogenated alkyl    group or an amino group;-   R1 represents a 2, 3 or 4-pyridine ring or a 2, 4 or 5-pyrimidine    ring, the rings being optionally substituted by a C₁₋₄ alkyl group,    a C₁₋₄ alkoxy group, or a halogen atom;-   R2 represents a phenyl group or a naphthalene ring; the phenyl group    and the naphthalene ring being optionally substituted by 1 to 4    substituents selected from a C₁₋₆ alkyl group, a methylenedioxy    group, a halogen atom, a C₁₋₂ perhalogenated alkyl group, a C₁₋₃    halogenated alkyl group, a hydroxyl group, a C₁₋₄ alkoxy group, a    nitro, a cyano, an amino, a C₁₋₅ monoalkylamino group, a C₂₋₁₀    dialkylamino group, a phenyl group, a pyrrolidine ring, a piperidine    ring or an azepine ring;-   R3 represents a hydrogen atom or a C₁₋₆ alkyl group;-   R4 represents a phenyl group, a pyridinyl group or a naphthalene    ring, the groups and the ring being optionally substituted by 1 to 4    substituents selected from a C₁₋₆ alkyl group, a methylenedioxy    group, a halogen atom, a C₁₋₂ perhalogenated alkyl group, a C₁₋₃    halogenated alkyl group, a hydroxyl group, a C₁₋₄ alkoxy group, a    nitro, a cyano, an amino, a C₁₋₅ monoalkylamino group or a C₂₋₁₀    dialkylamino group;-   R5 represents a hydrogen atom, a C₁₋₆ alkyl group or a halogen atom;    n represent 0 to 3; and p+q=0-3.

According to another aspect of the present invention, there is provideda medicament comprising as an active ingredient a substance selectedfrom the group consisting of the pyrimidone derivatives represented byformula (I) and the physiologically acceptable salts thereof, and thesolvates thereof and the hydrates thereof. As preferred embodiments ofthe medicament, there are provided the aforementioned medicament whichis used for preventive and/or therapeutic treatment of diseases causedby abnormal GSK3β activity, and the aforementioned medicament which isused for preventive and/or therapeutic treatment of neurodegenerativediseases and in addition other diseases such as: non-insulin dependentdiabetes (such as diabetes type II) and obesity; manic depressiveillness; schizophrenia; alopecia; cancers such as breast cancer,non-small cell lung carcinoma, thyroid cancer, T or B-cell leukemia andseveral virus-induced tumors.

As further preferred embodiments of the present invention, there areprovided the aforementioned medicament wherein the diseases areneurodegenerative diseases and are selected from the group consisting ofAlzheimer's disease, Parkinson's disease, taupathies (e.g.frontotemporoparietal dementia, corticobasal degeneration, Pick'sdisease, progressive supranuclear palsy) and other dementia includingvascular dementia; acute stroke and others traumatic injuries;cerebrovascular accidents (e.g. age related macular degeneration); brainand spinal cord trauma; peripheral neuropathies; retinopathies andglaucoma, and the aforementioned medicament in the form ofpharmaceutical composition containing the above substance as an activeingredient together with one or more pharmaceutical additives.

The present invention further provides an inhibitor of GSK3β activitycomprising as an active ingredient a substance selected from the groupconsisting of the substituted pyrimidone derivatives of formula (I) andthe salts thereof, and the solvates thereof and the hydrates thereof.

According to further aspects of the present invention, there is provideda method for preventive and/or therapeutic treatment ofneurodegenerative diseases caused by abnormal GSK3β activity, whichcomprises the step of administering to a patient a preventively and/ortherapeutically effective amount of a substance selected from the groupconsisting of substituted pyrimidone derivatives of formula (I) and thephysiologically acceptable salts thereof, and the solvates thereof andthe hydrates thereof; and a use of a substance selected from the groupconsisting of the substituted pyrimidone derivatives of formula (I) andthe physiologically acceptable salts thereof, and the solvates thereofand the hydrates thereof for the manufacture of the aforementionedmedicament.

As used herein, the C₁₋₆ alkyl group represents a straight or branchedalkyl group having 1 to 6 carbon atoms, for example, methyl group, ethylgroup, n-propyl group, isopropyl group, n-butyl group, isobutyl group,sec-butyl group, tert-butyl group, n-pentyl group, isopentyl group,neopentyl group, 1,1-dimethylpropyl group, n-hexyl group, isohexylgroup, and the like;

The C₁₋₄ alkoxy group represents an alkyloxy group having 1 to 4 carbonatoms for example, methoxy group, ethoxy group, propoxy group,isopropoxy group, butoxy group, isobutoxy group, sec-butoxy group,tert-butoxy group, and the like;

The halogen atom represents a fluorine, chlorine, bromine or iodineatom;

The C₁₋₂ perhalogenated alkyl group represents an alkyl group whereinall of the hydrogens have been substituted by halogens, for example aCF₃or C₂F₅;

The C₁₋₃ halogenated alkyl group represents an alkyl group wherein atleast one hydrogen has not been substituted by a halogen atom;

The C₁₋₅ monoalkylamino group represents an amino group substituted byone C₁₋₆ alkyl group, for example, methylamino group, ethylamino group,propylamino group, isopropylamino group, butylamino group, isobutylaminogroup, tert-butylamino group, pentylamino group and isopentylaminogroup;

The C₂₋₁₀ dialkylamino group represents an amino group substituted bytwo C₁₋₅ alkyl groups, for example, dimethylamino group,ethylmethylamino group, diethylamino group, methylpropylamino group anddiisopropylamino group;

A leaving group L represents a group which could be easily cleaved andsubstituted, such a group may be for example a tosyl, a mesyl, a bromideand the like.

P+q=0 to 3, indicates that the addition of p and q equals 0, 1, 2 or 3.

The compounds represented by the aforementioned formula (I) may form asalt. Examples of the salt include, when an acidic group exists, saltsof alkali metals and alkaline earth metals such as lithium, sodium,potassium, magnesium, and calcium; salts of ammonia and amines such asmethylamine, dimethylamine, trimethylamine, dicyclohexylamine,tris(hydroxymethyl)-aminomethane, N,N-bis(hydroxyethyl)piperazine,2-amino-2-methyl-1-propanol, ethanolamine, N-methylglucamine, andL-glucamine; or salts with basic amino acids such as lysine,δ-hydroxylysine, and arginine. The base-addition salts of acidiccompounds are prepared by standard procedures well known in the art.

When a basic group exists, examples include salts with mineral acidssuch as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid; salts with organic acids such as methanesulfonic acid,benzenesulfonic acid, p-toluenesulfonic acid, acetic acid, propionicacid, tartaric acid, fumaric acid, maleic acid, malic acid, oxalic acid,succinic acid, citric acid, benzoic acid, mandelic acid, cinnamic acid,lactic acid, glycolic acid, glucoronic acid, ascorbic acid, nicotinicacid, and salicylic acid; or salts with acidic amino acids such asaspartic acid, and glutamic acid.

The acid-addition salts of the basic compounds are prepared by standardprocedures well know in the art which include, but are not limitedthereto, dissolving the free base in an aqueous alcohol solutioncontaining the appropriate acid and isolating the salt by evaporatingthe solution, or by reacting the free base and an acid in an organicsolvent, in which case the salt separates directly, or is precipitatedwith a second organic solvent, or can be obtained by concentration ofthe solution. The acids which can be used to prepare the acid-additionsalts include preferably those which produce, when combined with thefree base, pharmaceutically-acceptable salts, that is, salts whoseanions are relatively innocuous to the animal organism in pharmaceuticaldoses of the salts, so that the beneficial properties inherent in thefree base are not compromised by side effects ascribable to the anions.Although medicinally acceptable salts of the basic compounds arepreferred, all acid-addition salts are within the scope of the presentinvention.

In addition to the substituted pyrimidone derivatives represented by theaforementioned formula (I) and salts thereof, their solvates andhydrates also fall within the scope of the present invention.

The substituted pyrimidone derivatives represented by the aforementionedformula (I) may have one or more asymmetric carbon atoms. As for thestereochemistry of such asymmetric carbon atoms, they may independentlybe in either (R) and (S) configuration, and the derivative may exist asstereoisomers such as optical isomers, or diastereoisomers. Anystereoisomers in pure form, any mixtures of stereoisomers, racemates andthe like fall within the scope of the present invention.

Examples of compounds of the present invention are shown in table 1hereinafter. However, the scope of the present invention is not limitedby these compounds.

One of the embodiments of the present invention include also compoundsrepresented by formula (I) wherein R1, R2, R3, R4, R5, X, Y, n, p and qare as defined hereunder:

-   (1) R1 represents a 3- or 4-pyridine ring and more preferably    4-pyridinyl ring or a 4- or 5-pyrimidine ring and more preferably    4-pyrimidinyl ring, which may be substituted by a C₁₋₂ alkyl group,    a C₁₋₂ alkoxy group or a halogen atom;-   (2) R2 represents a phenyl group or a naphthalene ring, the phenyl    group and the naphthalene ring being optionally substituted 1 to 4    substituents selected from a C₁₋₃ alkyl group, a halogen atom, a    hydroxyl group, a C₁₋₂ alkoxy group, a phenyl group, a pyrrolidine    ring, a piperidine ring or an azepine ring;-   (3) R3 represents a hydrogen atom;-   (4) R4 represents a phenyl group, a pyridinyl group or a naphthalene    ring;-   (5) R5 represents a hydrogen atom;-   (6) X represents two hydrogen atoms;-   (7) Y represents a carbonyl group or methylene group being    optionally substituted by one or two groups chosen from a C₁₋₃ alkyl    group, a hydroxyl group, a C₁₋₄ alkoxy group, a C₁₋₂ perhalogenated    alkyl group, an amino group;-   (8) n, p and q represent 0, 2 and 0, respectively.

Another embodiment of the present invention include compoundsrepresented by formula (I) wherein R1, R2, R3, R4, R5, X, Y, n, p and qare as defined hereunder:

-   (1) R1 represents an unsubstituted 4-pyridinyl ring or 4-pyrimidinyl    ring;    -   alternatively R1 represents an unsubstituted 4-pyridinyl ring;-   (2) R2 represents a phenyl group or a naphthalene ring, the phenyl    group and the naphthalene ring being optionally substituted by 1 to    4 substituents selected from a C₁₋₃ alkyl group, a halogen atom, a    hydroxyl group, a C₁₋₂ alkoxy group, a phenyl group, a pyrrolidine    ring, a piperidine ring or an azepine ring;-   (2) R3 represents a hydrogen atom;-   (3) R4 represents a phenyl group or a pyridinyl group;-   (4) R5 represents a hydrogen atom;-   (5) X represents two hydrogen atoms;-   (6) Y represents a carbonyl group or a methylene group optionally    substituted by a hydroxyl group;-   (7) n, p and q represent 0, 2 and 0, respectively.

Particularly compounds of the present invention represented by formula(I), wherein R4 is a 8-phenyl or a 8-pyridinyl group, include compoundsof Table 1:

-   1.    1′-[(2S)-2-Hydroxy-2-phenyl-ethyl]-8-phenyl-2-(4-pyridinyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4    -one-   2.    9-(2-Oxo-2-phenyl-ethyl)-8-phenyl-2-(4-pyridinyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one-   3.    9-[2-(3-Bromo-phenyl)-2-oxo-ethyl]-8-phenyl-2-(4-pyridinyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one-   4.    9-[2-(4-Chloro-phenyl)-2-oxo-ethyl]-8-phenyl-2-(4-pyridinyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one-   5.    9-[2-(4-Fluoro-phenyl)-2-oxo-ethyl]-8-phenyl-2-(4-pyridinyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one-   6.    9-[2-(3-Fluoro-phenyl)-2-oxo-ethyl]-8-phenyl-2-(4-pyridinyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one-   7.    9-[2-(4-Methoxy-phenyl)-2-oxo-ethyl]-8-phenyl-2-(4-pyridinyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one-   8.    9-[2-(Oxo-2-(4-pyrrolidin-1-yl-phenyl)-ethyl]-8-phenyl-2-(4-pyridinyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one-   9.    9-(2-Biphenyl-4-yl-2-oxo-ethyl)-8-phenyl-2-(4-pyridinyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one-   10.    9-(2-Oxo-2-p-tolyl-ethyl)-8-phenyl-2-(4-pyridinyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one-   11.    9-(2-Naphthalen-2-yl-2-oxo-ethyl)-8-phenyl-2-(4-pyridiny)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one-   12.    9-[2-(3-Methoxy-phenyl)-2-oxo-ethyl]-8-phenyl-2-(4-pyridinyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one-   13.    9-[2-(2-Methoxy-phenyl)-2-oxo-ethyl]-8-phenyl-2-(4-pyridinyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one-   14. 9-[(2S)-2-Oxo-2-phenyl-ethyl]-2,8-dipyridin    -4-y-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one-   15.    9-[2-(3-Bromo-phenyl)-2-oxo-ethyl]-2,8-dipyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one-   16.    9-(2-Hydroxy-2-phenyl-ethyl)-2,8-dipyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one-   17.    9-[2-(3-Bromo-phenyl)-2-hydroxy-ethyl]-2,8-dipyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one-   18.    9-[2-(3-Fluoro-phenyl)-2-oxo-ethyl]-2,8-dipyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one-   19.    9-[2-Hydroxy-2-(4-methoxy-phenyl)-ethyl]-8-phenyl-2-pyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one-   20.    9-(2-Hydroxy-2-p-tolyl-ethyl)-8-phenyl-2-pyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one-   21.    (−)-9-(2-Oxo-2-phenyl-ethyl)-2,8-dipyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1.2-a]pyrimidin-4-one-   22.    (+)-9-(2-Oxo-2-phenyl-ethyl)-2,8-dipyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1.2-a]pyrimidin-4-one-   23.    9-[2-Hydroxy-2-(3-bromo-phenyl)-ethyl]-8-phenyl-2-pyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one-   24.    9-[2-Hydroxy-2-(4-chloro-phenyl)-ethyl]-8-phenyl-2-pyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one-   25.    9-[2-(3-Fluoro-phenyl)-2-hydroxy-ethyl]-2,8-dipyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one-   26.    9-[2-Hydroxy-2-(4-fluoro-phenyl)-ethyl]-8-phenyl-2-pyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one-   27.    9-[2-Hydroxy-2-(4-phenyl-phenyl)-ethyl]-8-phenyl-2-pyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;    and-   28.    9-[2-Hydroxy-2-naphthalen-2-yl-ethyl]-8-phenyl-2-pyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one

As a further object, the present invention concerns also methods forpreparing the substituted pyrimidone compounds represented by theaforementioned formula (I). These compounds can be prepared, forexample, according to methods explained below.

Preparation Method

Substituted pyrimidone compounds represented by the aforementionedformula (I), may be prepared according to the method described in thescheme 1.

Following this method, the pyrimidinone derivative represented by theabove formula (III), wherein R1, R3, R4, R5, p and q are as defined forcompound of formula (I), is allowed to react with a base such as sodiumhydride, sodium carbonate or potassium carbonate in a solvent such asN,N-dimethylformamide, N-methylpyrrolidone, N,N-dimethylacetamide orchloroform at a suitable temperature ranging from 0 to 130° C. underordinary air, then with a compound of formula (II), wherein R2, X, Y andn are as defined for compound of formula (I) and L represents a leavinggroup preferably bromide or mesyl group, to obtain the compound of theaforementioned formula (I).

Alternatively compounds of formula (I) wherein Y represents a carbonylgroup may be prepared by oxidation of a compound of formula (I) whereinY represents a methylene group substituted by a hydroxyl group accordingto well known methods to one skilled in the art.

Compound of formula (II) is commercially available or may be synthesizedaccording to well-known methods to one skilled in the art.

Compound of formula (III) may be prepared according to the methoddefined in scheme 2.

In the above scheme, L represents a leaving group, preferably a bromideor a mesyl group.

According to this method, the 3-ketoester of formula (IV), wherein R1and R5 are as defined for compound of formula (I) and R is an alkylgroup such as for example methyl or ethyl, is allowed to react with acompound of formula (V), wherein R3, R4, p and q are the same as thosealready described for compound of formula (I). The reaction may becarried out in the presence of a base such as potassium carbonate, in analcoholic solvent such as methanol, ethanol and the like or without, ata suitable temperature ranging from 25° to 140° C. under ordinary air.

Alternatively, compound of formula (III) wherein R5 represents ahydrogen atom may be halogenated in order to give compounds of formula(III) wherein R5 is a halogen atom such as a bromine atom or a chlorineatom. The reaction may be carried out in an acidic medium such as aceticacid or propionic acid, in presence of bromosuccinimide orchlorosuccinimide, or bromine.

In addition, compounds of formula (III) wherein R5 represents a fluorineatom may be obtained by analogy to the method described in TetrahedronLetters, Vol. 30, No. 45, pp 6113-6116, 1989.

Compound of formula (IV) is commercially available or may be synthesizedaccording to well-known methods to one skilled in the art.

For example compounds of formula (IV), wherein R1 represent a pyridinering or a pyrimidine ring, optionally substituted by a C₁₋₄ alkyl group,C₁₋₄ alkoxy group or a halogen atom, can be prepared by reactingrespectively an isonicotinic acid or a pyrimidine-carboxylic acid,optionally substituted by a C₁₋₄ alkyl group, C₁₋₄ alkoxy group or ahalogen, with the corresponding malonic acid monoester. The reaction canbe carried out using methods well known to one skilled in the art, suchas for example in presence of a coupling agent such as1,1′-carbonylbis-1H-imidazole in a solvent such as tetrahydrofuran at atemperature ranging from 20 to 70° C.

In the above reactions, protection or deprotection of a functional groupmay sometimes be necessary. A suitable protecting group Pg can be chosendepending on the type of the functional group, and a method described inthe literature may be applied. Examples of protecting groups, ofprotection and deprotection methods are given for example in Protectivegroups in Organic Synthesis Greene et al., 2nd Ed. (John Wiley & Sons,Inc., New York).

Compound of formula (V) is commercially available or may be synthesizedaccording to well-known methods to one skilled in the art.

Alternatively, compound of formula (V), wherein p represents 2 and qrepresents 0, may be prepared according to the method defined in scheme3. In the scheme 3 below, Pg represents an amino-protecting group and La leaving group, preferably a bromide group or mesyl group.

According to this method, compound of formula (VI), wherein R4 isdefined as for compound of formula (I), may be obtained throughdifferent manners, depending on R3.

The 3-aminoacid of formula (VI), wherein R3 is a hydrogen atom, may besynthesized by analogy to the method described in Tetrahedron Letters,Vol. 43, No. 11, pp 1977-1981, 2002.

The 3-aminoacid of formula (VI), wherein R3 is a C₁₋₆ alkyl group, maybe synthesized by analogy to the method described in Journal of OrganicChemistry, Vol. 56, No. 1, pp 4-6, 1991.

In both cases, an amino-protecting group is necessary. Examples ofprotection and deprotection methods are given for example in Protectivegroups in Organic Synthesis Greene et al., 2nd Ed. (John Wiley & Sons,Inc., New York).

By analogy to these methods, compounds of formula (VII) and (VIII) maybe obtained by amino protection and compound of formula (IX) may beobtained by deprotection.

Then, compound of formula (V) may be obtained by cyclization, accordingto well-known methods to one skilled in the art.

Alternatively, if R3 represents H, compound of formula (V) may beobtained by hydrogenation of compound of formula (X), according towell-known methods to one skilled in the art.

Compound of formula (X) is commercially available or may be synthesizedaccording to well-known methods to one skilled in the art.

As a further object, the present invention concerns also the compound offormula (III) as intermediate for preparing compounds of formula (I).

The compounds of the present invention have inhibitory activity againstGSK3β. Accordingly, the compounds of the present invention are useful asan active ingredient for the preparation of a medicament, which enablespreventive and/or therapeutic treatment of a disease caused by abnormalGSK3β activity and more particularly of neurodegenerative diseases suchas Alzheimer's disease. In addition, the compounds of the presentinvention are also useful as an active ingredient for the preparation ofa medicament for preventive and/or therapeutic treatment ofneurodegenerative diseases such as Parkinson's disease, taupathies (e.g.frontotemporoparietal dementia, corticobasal degeneration, Pick'sdisease, progressive supranuclear palsy) and other dementia includingvascular dementia; acute stroke and others traumatic injuries;cerebrovascular accidents (e.g. age related macular degeneration); brainand spinal cord trauma; peripheral neuropathies; retinopathies andglaucoma; and other diseases such as non-insulin dependent diabetes(such as diabetes type II) and obesity; manic depressive illness;schizophrenia; alopecia; cancers such as breast cancer, non-small celllung carcinoma, thyroid cancer, T or B-cell leukemia and severalvirus-induced tumors.

The present invention further relates to a method for treatingneurodegenerative diseases caused by abnormal activity of GSK3β and ofthe aforementioned diseases which comprises administering to a mammalianorganism in need thereof an effective amount of a compound of theformula (I).

As the active ingredient of the medicament of the present invention, asubstance may be used which is selected from the group consisting of thecompound represented by the aforementioned formula (I) andpharmacologically acceptable salts thereof, and solvates thereof andhydrates thereof. The substance, per se, may be administered as themedicament of the present invention, however, it is desirable toadminister the medicament in a form of a pharmaceutical compositionwhich comprises the aforementioned substance as an active ingredient andone or more pharmaceutical additives. As the active ingredient of themedicament of the present invention, two or more of the aforementionedsubstances may be used in combination. The above pharmaceuticalcomposition may be supplemented with an active ingredient of anothermedicament for the treatment of the above mentioned diseases. The typeof pharmaceutical composition is not particularly limited, and thecomposition may be provided as any formulation for oral or parenteraladministration. For example, the pharmaceutical composition may beformulated, for example, in the form of pharmaceutical compositions fororal administration such as granules, fine granules, powders, hardcapsules, soft capsules, syrups, emulsions, suspensions, solutions andthe like, or in the form of pharmaceutical compositions for parenteraladministrations such as injections for intravenous, intramuscular, orsubcutaneous administration, drip infusions, transdermal preparations,transmucosal preparations, nasal drops, inhalants, suppositories and thelike. Injections or drip infusions may be prepared as powderypreparations such as in the form of lyophilized preparations, and may beused by dissolving just before use in an appropriate aqueous medium suchas physiological saline. Sustained-release preparations such as thosecoated with a polymer may be directly administered intracerebrally.

Types of pharmaceutical additives used for the manufacture of thepharmaceutical composition, content ratios of the pharmaceuticaladditives relative to the active ingredient, and methods for preparingthe pharmaceutical composition may be appropriately chosen by thoseskilled in the art. Inorganic or organic substances, or solid or liquidsubstances may be used as pharmaceutical additives. Generally, thepharmaceutical additives may be incorporated in a ratio ranging from 1%by weight to 90% by weight based on the weight of an active ingredient.

Examples of excipients used for the preparation of solid pharmaceuticalcompositions include, for example, lactose, sucrose, starch, talc,cellulose, dextrin, kaolin, calcium carbonate and the like. For thepreparation of liquid compositions for oral administration, aconventional inert diluent such as water or a vegetable oil may be used.The liquid composition may contain, in addition to the inert diluent,auxiliaries such as moistening agents, suspension aids, sweeteners,aromatics, colorants, and preservatives. The liquid composition may befilled in capsules made of an absorbable material such as gelatin.Examples of solvents or suspension mediums used for the preparation ofcompositions for parenteral administration, e.g. injections,suppositories, include water, propylene glycol, polyethylene glycol,benzyl alcohol, ethyl oleate, lecithin and the like. Examples of basematerials used for suppositories include, for example, cacao butter,emulsified cacao butter, lauric lipid, witepsol.

The dose and frequency of administration of the medicament of thepresent invention are not particularly limited, and they may beappropriately chosen depending on conditions such as a purpose ofpreventive and/or therapeutic treatment, a type of a disease, the bodyweight or age of a patient, severity of a disease and the like.Generally, a daily dose for oral administration to an adult may be 0.01to 1,000 mg (the weight of an active ingredient), and the dose may beadministered once a day or several times a day as divided portions, oronce in several days. When the medicament is used as an injection,administrations may preferably be performed continuously orintermittently in a daily dose of 0.001 to 100 mg (the weight of anactive ingredient) to an adult.

CHEMICAL EXAMPLES

The present invention will be explained more specifically with referenceto the following general examples, however, the scope of the presentinvention is not limited to these examples.

Example 1 (Compound No. 2 of Table 1)9-(2-Oxo-2-phenyl-ethyl)-8-phenyl-2-(4-pyridinyl)-6,7,8,9-tetrahydro-4H-pyrimido[1.2-a]pyrimidin-4-onehydrochloride (1:1) 1.1 6-Phenyl-1,4,5,6-tetrahydro-2-pyrimidinaminehydrochloride (1:2)

To a solution of 5 g (29.2 mmoles) of 2-amino-4-phenylpyrimidine in 30ml of a 6N solution of hydrochloric acid in isopropanol was added 0.1 gof palladium on carbon catalyst (10% wt/wt). The suspension washydrogenated under 40 psi pressure at room temperature during 3 h. Thecatalyst was removed by filtration and the solvent evaporated underreduced pressure. Diethyl ether was added and the resulting solution wasrefiltered and the solvent removed by evaporation under reduced pressureto give 4.0 g (55%) of compound as a crude oil which was used as such.

1.28-Phenyl-2-(4-pyridinyl)-6,7,8,9-tetrahydro-4H-pyrimido[1.2-a]pyrimidin-4-one

A suspension containing 4 g (16.12 mmoles) of6-phenyl-1,4,5,6-tetrahydro-2-pyrimidinamine hydrochloride (1:2), 3.11 g(16.12 mmoles) of ethyl 3-(pyridin-4-yl)-3-oxopropionate, 6.68 g (48.36mmoles) of anhydrous potassium carbonate in 50 ml of ethanol wererefluxed for 18 h. The cooled solution was evaporated and the residuewas treated with water and allowed to stir at 0° C. during 2 h. Theprecipitate which formed was recovered by filtration and dried at 90° C.during 18 h. 4.80 g (98%) of product was thus obtained.

1.39-(2-Oxo-2-phenyl-ethyl)-8-phenyl-2-(4-pyridinyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-onehydrochloride (1:1)

A solution of 0.3 g (98 mmoles) of8-phenyl-2-(4-pyridinyl)-6,7,8,9-tetrahydro-4H-pyrimido[1.2-a]pyrimidin-4-onein 8 ml of anhydrous dimethylformamide was treated with 51 mg (1.28mmoles) of sodium hydride (60% in mineral oil). The resulting suspensionwas stirred at 0° C. for 30 mins and then treated with 0.255 g (1.28mmoles) of 2-bromoacetophenone. After stirring for 18 h at roomtemperature, water was added and the reaction mixture was extracted withethyl acetate. The organic phase was washed with a saturated solution ofaqueous sodium chloride and was evaporated under reduced pressure togive crude product. Purification using silica gel chromatography elutingwith a gradient comprising dichloromethane/methanol in the proportions99/1 to 95/5 gave pure product which was dissolved in ethanol andtreated with 1 equivalent of a solution of hydrochloric acid inisopropanol. The resulting salt was recrystallized from a mixture ofisopropanol/diisopropylether to give 0.16 g (39%) of pure product. Mp:134-137° C.

¹H NMR (200 MHz; DMSO-d⁶): δ (ppm) 8.6 (d, 2H); 8.0 (d, 2H); 7.6 (d,1H); 7.5 (t, 2H); 7.3 (m, 5H); 6.6 (s, 1H); 5.7 (d, 1H); 5.1 (br s, 1H);4.5 (m, 2H); 3.2 (ddd, 1H); 2.2 (m, 2H).

Example 2 (Compound No. 1 of Table 1)1′-[(2S)-2-Hydroxy-2-phenyl-ethyl]-8-phenyl-2-(4-pyridinyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-onehydrochloride (1:1)

The product was obtained by analogy with the method described in Example1.3, but replacing 2-bromoacetophenone by (1S)-2-chloro-1-phenylethanol. Mp: 254-256° C.

¹H NMR (200 MHz; DMSO-d⁶): δ (ppm) 8.9 (m, 2H); 8.3 (m, 2H); 7.5-7.1 (m,10H); 6.6 (m, 1H); 5.3-5.0 (m, 2H); 4.6-4.0 (m, 3H); 3.2-2.7 (m, 2H);2.5-1.8 (m, 2H).

Example 3 (Compound No. 3 of Table 1)9-[2-(3-Bromo-phenyl)-2-oxo-ethyl]-8-phenyl-2-(4-pyridinyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-onehydrochloride (1:1)

The product was obtained by analogy with the method described in Example1.3, but replacing 2-bromoacetophenone by 3-bromo-(2-bromoacetophenone).Mp: 143-145° C.

¹H NMR (200 MHz; DMSO-d⁶): δ (ppm) 8.7 (d, 2H); 8.2-7.8 (m, 5H); 7.5-7.2(m, 7H); 6.6 (s, 1H); 5.7 (d, 1H); 5.1 (br s, 1H); 4.5 (d, 1H); 4.3 (m,1H); 3.2 (ddd, 1H); 2.4-2.1 (m, 2H).

Example 4 (Compound No. 4 of Table 1)9-[2-(4-Chloro-phenyl)-2-oxoethyl]-8-phenyl-2-(4-pyridinyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-onehydrochloride (1:1)

The product was obtained by analogy with the method described in Example1.3, but replacing 2-bromoacetophenone by4-chloro-(2-bromoacetophenone). Mp: 145-147° C.

¹H NMR (200 MHz; DMSO-d⁶): δ (ppm) 8.7 (d, 2H); 8.1 (m, 4H); 7.6 (d,2H); 7.4 (m, 5H); 6.7 (s, 1H); 5.7 (d, 1H); 5.1 (br s, 1H); 4.5 (d, 1H);4.3 (m, 1H); 3.2 (ddd, 1H); 2.4-2.1 (m, 2H).

Example 5 (Compound No. 5 of Table 1)9-[2-(4-Fluoro-phenyl)-2-oxo-ethyl]-8-phenyl-2-(4-pyridinyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-onehydrochloride (1:1)

The product was obtained by analogy with the method described in Example1.3, but replacing 2-bromoacetophenone by4-fluoro-(2-bromoacetophenone). Mp: 145-147° C.

¹H NMR (200 MHz; DMSO-d⁶): δ (ppm) 8.7 (d, 2H); 8.1 (m, 4H); 7.6 (m,8H); 6.6 (s, 1H); 5.7 (d, 1H); 5.1 (br s, 1H); 4.5 (m, 1H); 4.3 (br s,1H); 3.2 (ddd, 1H); 2.4-2.1 (m, 2H).

Example 6 (Compound No. 6 of Table 1)9-[2-(3-Fluoro-phenyl)-2-oxo-ethyl]-8-phenyl-2-(4-pyridinyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-onehydrochloride (1:1)

The product was obtained by analogy with the method described in Example1.3, but replacing 2-bromoacetophenone by3-fluoro-(2-bromoacetophenone). Mp: 167-169° C.

¹H NMR (200 MHz; DMSO-d⁶): δ (ppm) 8.7 (d, 2H); 8.1 (d, 2H); 7.8 (m,2H); 7.6-7.2 (m, 7H); 6.6 (s, 1H); 5.7 (d, 1H); 5.1 (br s, 1H); 4.5 (d,1H); 4.4 (m, 1H); 3.2 (ddd, 1H); 2.4-2.1 (m, 2H).

Example 7 (Compound No. 7 of Table 1)9-[2-(4-Methoxy-phenyl)-2-oxo-ethyl]-8-phenyl-2-(4-pyridinyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-onehydrochloride (1:1)

The product was obtained by analogy with the method described in Example1.3, but replacing 2-bromoacetophenone by4-methoxy-(2-bromoacetophenone). Mp: 197-199° C.

¹H NMR (200 MHz; CDCl₃): δ (ppm) 8.5 (d, 2H); 8.0 (d, 2H); 7.6-7.2 (m,7H); 7.0 (d, 2H); 6.5 (s, 1H); 5.8 (d, 1H); 5.0 (dd, 1H); 4.5 (m, 1H);4.1 (d, 1H); 3.9 (s, 3H); 3.5 (ddd, 1H); 2.6 (m, 1H); 2.3 (m, 1H).

Example 8 (Compound No. 8 of Table 1)9-[2-(Oxo-2-(4-pyrrolidin-1-yl-phenyl)-ethyl]-8-phenyl-2-(4-pyridinyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one

The product was obtained by analogy with the method described in Example1.3, but replacing 2-bromoacetophenone by4-N-pyrrolidinyl-(2-bromoacetophenone). Mp: 253-255° C.

¹H NMR (200 MHz; CDCl₃): δ (ppm) 8.5 (d, 2H); 7.9 (d, 2H); 7.6 (d, 2H);7.5-7.3 (m, 7H); 6.6 (d, 2H); 6.4 (s, 1H); 5.9 (d, 1H); 5.0 (br s, 1H);4.5 (m, 1H); 4.1 (d, 1H); 3.6-3.3 (m, 5H); 2.6 (m, 1H); 2.3-2.0 (m, 5H).

Example 9 (Compound No. 9 of Table 1)9-(2-Biphenyl-4-yl-2-oxo-ethyl)-8-phenyl-2-(4-pyridinyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one

The product was obtained by analogy with the method described in Example1.3, but replacing 2-bromoacetophenone by4-phenyl-(2-bromoacetophenone). Mp: 222-224° C.

¹H NMR (200 MHz; CDCl₃): δ (ppm) 8.5 (d, 2H); 8.2 (d, 2H); 7.8-7.6 (m,4H); 7.5-7.3 (m, 8H); 7.2 (d, 2H); 6.5 (s, 1H); 5.9 (d, 1H); 5.0 (br s,1H); 4.5 (m, 1H); 4.2 (d, 1H); 3.6 (ddd, 1H); 2.7 (m, 1H); 2.3 (m, 1H).

Example 10 (Compound No. 10 of Table 1)9-(2-Oxo-2-p-tolyl-ethyl)-8-phenyl-2-(4-pyridinyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one

The product was obtained by analogy with the method described in Example1.3, but replacing 2-bromoacetophenone by4-methyl-(2-bromoacetophenone). Mp: 209-211° C.

¹H NMR (200 MHz; CDCl₃): δ (ppm) 8.5 (d, 2H); 7.9 (d, 2H); 7.6-7.2 (m,9H); 6.5 (s, 1H); 5.8 (d, 1H); 4.9 (br s, 1H); 4.5 (m, 1H); 4.1 (d, 1H);3.6 (ddd, 1H); 2.6 (m, 1H); 2.5 (s, 3H); 2.2(m, 1H).

Example 11 (Compound No. 11 of Table 1)9-(2-Naphthalen-2-yl-2-oxo-ethyl)-8-phenyl-2-(4-pyridinyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one

The product was obtained by analogy with the method described in Example1.3, but replacing 2-bromoacetophenone by 2-bromoacetylnaphthalene. Mp:226-228° C.

¹H NMR (200 MHz; CDCl₃): δ (ppm) 8.6 (s, 1 H); 8.4 (d, 2H); 8.1-7.9 (m,4H); 7.7-7.5 (m, 2H); 7.4-7.2 (m, 7H); 6.45 (s, 1H); 6.0 (d, 1H); 5.0(br s, 1H); 4.6 (m, 1H); 4.3 (d, 1H); 3.6 (ddd, 1H); 2.7 (m, 1H); 2.3(m, 1H).

Example 12 (Compound No. 12 of Table 1)9-[2-(3-Methoxy-phenyl)-2-oxo-ethyl]-8-phenyl-2-(4-pyridinyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one

The product was obtained by analogy with the method described in Example1.3, but replacing 2-bromoacetophenone by3-methoxy-(2-bromoacetophenone). Mp: 216-218° C.

¹H NMR (200 MHz; CDCl₃): δ (ppm) 8.5 (d, 2H); 7.7-7.2 (m, 11H); 6.45 (s,1H); 5.85 (d, 1H); 4.9 (brs, 1H); 4.65 (m, 1H); 4.15 (d, 1H); 3.85 (s,3H); 2.55 (ddd, 1H); 2.65 (m, 1H); 2.3 (m, 1H).

Example 13 (Compound No. 13 of Table 1)9-[2-(2-Methoxy-phenyl)-2-oxo-ethyl]-8-phenyl-2-(4-pyridinyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one

The product was obtained by analogy with the method described in Example1.3, but replacing 2-bromoacetophenone by2-methoxy-(2-bromoacetophenone). Mp: 142-144° C.

¹H NMR (200 MHz; DMSO-d⁶): δ (ppm) 8.7 (d, 2H); 8.0 (d, 2H); 7.6 (m,2H); 7.4 (m, 5H); 7.2 (d, 1H); 7.1 (t, 1H); 6.6 (s, 1H); 5.5 (d, 1H);5.0 (br s, 1H); 4.3 (d, 2H); 3.8 (s, 3H); 3.5 (m, 1H); 3.3 (ddd, 1H);2.4-2.1 (m, 2H).

Example 14 (Compound No. 14 of Table 1)9-[(2S)-2-Oxo-2-phenyl-ethyl]-2,8-dipyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-onehydrochloride (1:2) 14.16-(4-Pyridinyl)-1,4,5,6-tetrahydro-2-pyrimidinamine hydrochloride (1:2)

To a solution of 5 g (29.2 mmoles) of 2-amino-4-(4-pyrimidyl)-pyrimidine(Journal of Medicinal Chemistry (1978), 21(7), 623-8) in 30 ml of a 6Nsolution of hydrochloric acid in isopropanol was added 5 ml of water and0.2 g of palladium on carbon catalyst (10% wt/wt). The suspension washydrogenated under 40 psi pressure at 50° C. temperature during 8 h. Thecatalyst was removed by filtration and the solvent evaporated underreduced pressure. Isopropanol was added and the resulting solution wasrefiltered and the solvent removed by evaporation under reduced pressureto give 2.0 g (27%) of compound as a white powder which was used assuch.

14.22,8-Dipyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one

A suspension containing 1.0 g (4.01 mmoles) of6-(4-pyridinyl)-1,4,5,6-tetrahydro-2-pyrimidinamine dihydrochloride in30 ml of ethanol was treated with 1.94 g (14.05 mmoles) of potassiumcarbonate and allowed to stir for 5 min. 1.0 g (4.01 mmoles) of ethyl3-(pyridin-4-yl)-3-oxopropionate were added and the resulting mixturewas heated at reflux temperature for 18 h. The cooled solution wasevaporated to remove solvent and the residue was dissolved in water andextracted with dichloromethane. The organic extracts were washed with asaturated solution of aqueous sodium chloride, dried and the solventevaporated under reduced pressure. The crude product thus obtained waspurified using silica gel chromatography eluting with a gradient ofdichloromethane/methanol/concentrated aqueous ammonia solution in theproportions 95/5/0.5 to 80/20/2. 0.26 g (21%) of pure product wasobtained. Mp: 268-270° C.

14.39-[(2S)-2-Oxo-2-phenyl-ethyl]-2,8-dipyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-onehydrochloride (1:2)

A suspension of 0.30 g (0.98 mmole) of2,8-di-4-pyridinyl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-onein 6 ml of dimethylformamide was treated with 51 mg (1.28 mmole) ofsodium hydride (60% in mineral oil) and the resulting suspension stirredat 35° C. for 30 mins. The mixture was then cooled to 0° C. and wastreated with 0.235 g (1.18 mmole) of 2-bromoacetophenone and stirred for4 h at room temperature. Water was added and the mixture extracted withdichloromethane. The organic extracts were washed with a saturatedaqueous solution of sodium chloride and dried and evaporated. The crudeproduct thus obtained was purified using silica gel chromatographyeluting with a gradient of dichloromethane/methanol in the proportions99/1 to 90/10. The pure product obtained was then dissolved in ethanoland treated with 1 equivalent of a solution of hydrochloric acid inisopropanol to give the hydrochloride salt. The resulting salt wasrecrystallized from a mixture of isopropanol/diisopropylether to give0.20 g (48%) of pure product. Mp: 246-248° C.

¹H NMR (200 MHz; DMSO-d⁶): δ (ppm) 8.9 (d, 2H); 8.7 (d, 2H); 8.0 (m,6H); 7.8-7.5 (m, 3H); 6.7 (s, 1H); 5.75 (d, 1H); 5.3 (br s, 1H); 4.7 (d,1H); 4.5 (m, 1H); 3.1 (ddd, 1H); 2.5 (m, 2H).

Example 15 (Compound No. 15 of Table 1)9-[2-(3-Bromo-phenyl)-2-oxo-ethyl]-2,8-dipyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-onehydrochloride (1:2)

The product was obtained by analogy with the method described in Example2.3, but replacing 2-bromoacetophenone by 3-bromo-(2-bromoacetophenone).Mp: 215-217° C.

¹H NMR (200 MHz; DMSO-d⁶): δ (ppm) 8.9 (d, 2H); 8.7 (d, 2H); 8.3-7.8 (m,7H); 7.5 (t, 1H); 6.7 (s, 1H); 5.75 (d, 1H); 5.3 (br s, 1H); 4.7 (d,1H); 4.5 (m, 1H); 3.1 (ddd, 1H); 2.5 (m, 2H).

Example 16 (Compound No. 16 of Table 1)9-(2-Hydroxy-2-phenyl-ethyl)-2,8-dipyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-onehydrochloride (1:2)

The product was obtained by analogy with the method described in Example2.3, but replacing 2-bromoacetophenone by (1-S)-2-chloro-1-phenylethanol.

Mp: 204-206° C.

¹H NMR (200 MHz; DMSO-d⁶): δ (ppm) 9.0 (m, 2H); 8.8 (m, 2H); 8.45 (m,2H); 7.9 (d, 1H); 7.8-7.6 (m, 1H); 7.5-7.2 (m, 5H); 6.8 (s, 1H); 6.2-5.7(br d, 1H); 5.3-5.1 (m, 1H); 4.6-4.1 (m, 2H); 3.3 (m, 2H); 2.9 (m, 1H);2.5-2.2 (m, 2H).

Example 17 (Compound No. 17 of Table 1)9-[2-(3-Bromo-phenyl)-2-hydroxy-ethyl]-2,8-dipyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one

The product was obtained by analogy with the method described in Example2.3, but replacing 2-bromoacetophenone by2-chloro-1-(3-bromo-phenyl)-ethanol. Mp: 190-192° C.

¹H NMR (200 MHz; CDCl₃): δ (ppm) 8.8 (d, 2H); 8.7 (d, 2H); 7.8 (m, 2H);7.7-7.4 (m, 2H); 7.3 (m, 2H); 7.1 (d, 2H); 6.5 (s, 1H); 5.2 (m, 2H);4.8-4.4 (m, 3H); 3.2 (m, 2H); 2.3 (m, 2H).

Example 18 (Compound No. 18 of Table 1)9-[2-(3-Fluoro-phenyl)-2-oxo-ethyl]-2,8-dipyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-oneone hydrochloride (1:2)

The product was obtained by analogy with the method described in Example2.3, but replacing 2-bromoacetophenone by3-fluoro-(2-bromoacetophenone). Mp: 132-134° C.

¹H NMR (200 MHz; DMSO-d⁶): δ (ppm) 8.9 (d, 2H); 8.7 (d, 2H); 8.1 (d,2H); 8.0 (d, 2H); 7.9-7.7 (m, 2H); 7.7-7.5 (m, 2H); 6.8 (s, 1H); 5.7 (d,2H); 5.3 (br s, 1H); 4.7 (d, 1H); 4.4 (m, 1H); 3.1 (ddd, 1H); 2.4 (m,1H).

Example 19 (Compound No. 19 of Table 1)9-[2-Hydroxy-2-(4-methoxy-phenyl)-ethyl]-8-phenyl-2-pyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one

The product was obtained by analogy with the method described in Example1.3, but replacing 2-bromoacetophenone by 2-chloro-1-(4-methoxy-phenyl)ethanol. Mp: 150-152° C.

¹H NMR (200 MHz; CDCl₃): δ (ppm) 8.8 (d, 2H); 7.9 (d, 2H); 7.6-7.2 (m,6H); 7.1 (m, 2H); 6.9 (m, 2H); 5.3-5.0 (m, 2H); 4.8-4.4 (m, 3H); 3.8 (m,3H); 3.4-3.0 (m, 2H); 2.4-2.0(m, 2H).

Example 20 (Compound No. 20 of Table 1)9-(2-Hydroxy-2-p-tolyl-ethyl)-8-phenyl-2-pyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one

The product was obtained by analogy with the method described in Example1.3, but replacing 2-bromoacetophenone by2-chloro-1-(4-methylphenyl)-ethanol. Mp: 198-200° C.

¹H NMR (200 MHz; CDCl₃): δ (ppm) 8.8 (d, 2H); 7.8 (d, 2H); 7.4-7.0 (m,8H); 6.5 (s, 1H); 5.2 (m, 1H); 4.8-4.4 (m, 5H); 3.4-3.0 (m , 2H);2.5-2.0 (m, 5H).

Example 21 (Compound No. 21 of Table 1)(−)-9-(2-Oxo-2-phenyl-ethyl)-2,8-dipyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-onehydrochloride (1:2) 21.1(+)-2,8-Dipyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one

1.2 g (3.93 mmol) of2,8-dipyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one(compound No. 14.2) was separated by chiral preparative HPLC (CHIRALPAKAS) eluting with n-heptane/ethanol in the proportions 50/50 to give0.572 g of pure product obtained in the form of free base. t_(R): 7 min.Mp: 235-238° C. [α]_(D) ²⁰=+11.3° (c=0.44, DMSO).

21.2(−)-9-(2-Oxo-2-phenyl-ethyl)-2,8-dipyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-onehydrochloride (1:2)

The product was obtained by analogy with the method described in Example14.3. Mp: 225-227° C. [α]_(D) ²⁰=−63.1° (c=0.356, DMSO).

¹H NMR (200 MHz; DMSO-d⁶): δ (ppm) 8.9 (d, 2H); 8.7 (d, 2H); 8.0 (m,6H); 7.8-7.5 (m, 3H); 6.7 (s, 1H); 5.75 (d, 1H); 5.3 (br s, 1H); 4.7 (d,1H); 4.5 (m, 1H); 3.1 (ddd, 1H); 2.5 (m, 2H).

Example 22 (Compound No. 22 of Table 1)(+)-9-(2-Oxo-2-phenyl-ethyl)-2,8-dipyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-onehydrochloride (1:2)22.1(−)-2,8-Dipyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one

1.2 g (3.93 mmol) of2,8-dipyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one(compound No. 14.2) was separated by chiral preparative HPLC (CHIRALPAKAS) eluting with n-heptane/ethanol in the proportions 50/50 to give0.572 g of pure product obtained in the form of free base. t_(R): 12min. Mp: 235-238° C. [α]_(D) ²⁰=−11.5° (c=0.394, DMSO).

22.2(+)-9-(2-Oxo-2-phenyl-ethyl)-2,8-dipyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-onehydrochloride (1:2)

The product was obtained by analogy with the method described in Example14.3. Mp: 225-227° C. [α]_(D) ²⁰=+65.4° (c=0.521, DMSO).

¹H NMR (200 MHz; DMSO-d⁶): δ (ppm) 8.9 (d, 2H); 8.7 (d, 2H); 8.0 (m,6H); 7.8-7.5 (m, 3H); 6.7 (s, 1H); 5.75 (d, 1H); 5.3 (br s, 1H); 4.7 (d,1H); 4.5 (m, 1 H); 3.1 (ddd, 1H); 2.5 (m, 2H).

A list of chemical structures and physical data for compounds of theaforementioned formula (I), illustrating the present invention, is givenin Table 1. The compounds have been prepared according to the methods ofthe examples.

In Table 1, R1 is an unsubstituted pyrimidin-4-yl group or anunsubstituted pyridin-4-yl group, p represents 2, q represents 0, Phrepresents a phenyl group, Me represents a methyl group; (+) and (−)indicates respectively a dextro and levo isomer; (S), (R) or (Rac.)indicates in the column “Y” or R4, the stereochemistry of the carbonatom: (rac.) means racemic mixture; (R) means absolute R configuration;(S) means absolute S configuration.

TABLE 1 (I)

No R2 Y X R1 R3 R4 R5 q p n Mp ° C. salt 1. Ph CH(OH)(S) H,H

H Ph(Rac.) H 0 2 0 254-256 (1:1)(hydro-chlo-ride) 2. Ph CO H,H

H Ph(Rac.) H 0 2 0 134-137 (1:1)(hydro-chlo-ride) 3. 3-Br-Ph CO H,H

H Ph(Rac.) H 0 2 0 143-145 (1:1)(hydro-chlo-ride) 4. 4-Cl-Ph CO H,H

H Ph(Rac.) H 0 2 0 145-147 (1:1)(hydro-chlo-ride) 5. 4-F-Ph CO H,H

H Ph(Rac.) H 0 2 0 145-147 (1:1)(hydro-chlo-ride) 6. 3-F-Ph CO H,H

H Ph(Rac.) H 0 2 0 167-169 (1:1)(hydro-chlo-ride) 7. 4-MeO-Ph CO H,H

H Ph(Rac.) H 0 2 0 197-199 (1:1)(hydro-chlo-ride) 8. 4-N-Pyrro-lidine-PhCO H,H

H Ph(Rac.) H 0 2 0 253-255 Base 9. 4-Ph-Ph CO H,H

H Ph(Rac.) H 0 2 0 222-224 Base 10. 4-Me-Ph CO H,H

H Ph(Rac.) H 0 2 0 209-211 Base 11. 2-Naphthyl CO H,H

H Ph(Rac.) H 0 2 0 226-228 Base 12. 3-MeO-Ph CO H,H

H Ph(Rac.) H 0 2 0 216-218 Base 13. 2-MeO-Ph CO H,H

H Ph(Rac.) H 0 2 0 142-144 Base 14. Ph CO H,H

H

H 0 2 0 246-248 Hydro-chlo-ride (1:2) 15. 3-Br-Ph CO H,H

H

H 0 2 0 215-217 Hydro-chlo-ride (1:2) 16. Ph (S)—CH(OH) H,H

H

H 0 2 0 204-206 Hydro-chlo-ride (1:2) 17. 3-Br-Ph CH(OH)(Rac.) H,H

H

H 0 2 0 190-192 Hydro-chlo-ride (1:2) 18. 3-F-Ph CO H,H

H

H 0 2 0 132-134 Hydro-chlo-ride (1:2) 19. 4-MeO-Ph CH(OH)(Rac.) H,H

H Ph(Rac.) H 0 2 0 150-152 Base 20. 4-Me-Ph CH(OH)(Rac.) H,H

H Ph(Rac.) H 0 2 0 198-200 Base 21. Ph CO H,H

H

H 0 2 0 225-227 Hydro-chlo-ride (1:2) 22. Ph CO H,H

H

H 0 2 0 225-227 Hydro-chlo-ride (1:2) 23. 3-Br-Ph CH(OH)(Rac.) H,H

H Ph(Rac.) H 0 2 0 170-172 Base 24. 4-Cl-Ph CH(OH)(Rac.) H,H

H Ph(Rac.) H 0 2 0 220-222 Base 25. 3-F-Ph CH(OH)(Rac.) H,H

H

H 0 2 0 218-220 Base 26. 4-F-Ph CH(OH)(Rac.) H,H

H Ph(Rac.) H 0 2 0 201-203 Base 27. 4-Ph-Ph CH(OH)(Rac.) H,H

H Ph(Rac.) H 0 2 0 145-147 Base 28. 2-Naphthyl CH(OH)(Rac.) H,H

H Ph(Rac.) H 0 2 0 190-192 Base

Test Example

Inhibitory Activity of the Medicament of the Present Invention AgainstGSK3β:

Two different protocols can be used.

In a first protocol: 7.5 μM of prephosphorylated GS1 peptide and 10 μMATP (containing 300,000 cpm of 33P-ATP) were incubated in 25 mMTris-HCl, pH 7.5, 0.6 mM DTT, 6 mM MgCl₂, 0.6 mM EGTA, 0.05 mg/ml BSAbuffer for 1 hour at room temperature in the presence of GSK3beta (totalreaction volume: 100 microliters).

In a second protocol: 4.1 μM of prephosphorylated GS1 peptide and 42 μMATP (containing 260,000 cpm 33P-ATP) were incubated in 80 mM Mes-NaOH,pH 6.5, 1 mM Mg acetate, 0.5 mM EGTA, 5 mM 2-mercaptoethanol, 0.02%Tween 20, 10% glycerol buffer for 2 hours at room temperature in thepresence of GSK3beta. Inhibitors were solubilized in DMSO (final solventconcentration in the reaction medium, 1%).

The reaction was stopped with 100 microliters of a solution made of 25 gpolyphosphoric acid (85% P₂O₅), 126 ml 85% H₃PO₄, H₂O to 500 ml and thendiluted to 1:100 before use. An aliquot of the reaction mixture was thentransferred to Whatman P81 cation exchange filters and rinsed with thesolution described above. Incorporated 33P radioactivity was determinedby liquid scintillation spectrometry. The phosphorylated GS-1 peptidehad the following sequence:

-   NH2-YRRAAVPPSPSLSRHSSPHQS(P)EDEE-COOH. SEQ ID NO: 1

The GSK3β inhibitory activity of the compounds of the present inventionare expressed in IC₅₀, and as an illustration the range of IC₅₀'s of thecompounds in Table 1 is between 1 nanomolar to 1 micromolarconcentrations.

For example compound No. 15 of Table 1 shows an IC₅₀ of 0.007 μM.

Formulation Examples

(1) Tablets

The ingredients below were mixed by an ordinary method and compressed byusing a conventional apparatus.

Compound of Example 1 30 mg Crystalline cellulose 60 mg Corn starch 100mg Lactose 200 mg Magnesium stearate 4 mg(2) Soft Capsules

The ingredients below were mixed by an ordinary method and filled insoft capsules.

Compound of Example 1 30 mg Olive oil 300 mg Lecithin 20 mg(1) Parenteral Preparations

The ingredients below were mixed by an ordinary method to prepareinjections contained in a 1 ml ampoule.

Compound of Example 1 3 mg Sodium chloride 4 mg Distilled water forinjection 1 ml

INDUSTRIAL APPLICABILITY

The compounds of the present invention have GSK3β inhibitory activityand are useful as an active ingredient of a medicament for preventiveand/or therapeutic treatment of diseases caused by abnormal activity ofGSK3β and more particularly of neurodegenerative diseases.

1. A compound of formula (I) or a salt thereof

wherein: X represents two hydrogen atoms, a sulfur atom, an oxygen atomor a C₁₋₂ alkyl group and a hydrogen atom; Y represents a bond, acarbonyl group, a methylene group optionally substituted by one or twogroups chosen from a C₁₋₆ alkyl group, a hydroxyl group, a C₁₋₄ alkoxygroup, a C₁₋₂ perhalogenated alkyl group or an amino group; R1represents a 2, 3 or 4-pyridine ring or a 2, 4 or 5-pyrimidine ring, therings being optionally substituted by a C₁₋₄ alkyl group, a C₁₋₄ alkoxygroup or a halogen atom; R2 represents a phenyl group or a naphthalenering; the phenyl group or the naphthalene ring being optionallysubstituted by 1 to 4 substituents selected from a C₁₋₆ alkyl group, amethylenedioxy group, a halogen atom, a C₁₋₂ perhalogenated alkyl group,a C₁₋₃ halogenated alkyl group, a hydroxyl group, a C₁₋₄ alkoxy group, anitro, a cyano, an amino, a C₁₋₅ monoalkylamino group, a C₂₋₁₀dialkylamino group, a phenyl group, a pyrrolidine ring, a piperidinering or an azepine ring; R3 represents a hydrogen atom or a C₁₋₆ alkylgroup; R4 represents a phenyl group, a naphthalene ring or a pyridinylgroup, the groups and the ring being optionally substituted by 1 to 4substituents selected from a C₁₋₆ alkyl group, a methylenedioxy group, ahalogen atom, a C₁₋₂ perhalogenated alkyl group, a C₁₋₃ halogenatedalkyl group, a hydroxyl group, a C₁₋₄ alkoxy group, a nitro, a cyano, anamino, a C₁₋₅ monoalkylamino group or a C₂₋₁₀ dialkylamino group; R5represents a hydrogen atom, a C₁₋₆ alkyl group or a halogen atom; nrepresents 0 to 3; and p+q=0-3.
 2. The compound of formula (I) accordingto claim 1, wherein R4 represents a phenyl group or a pyridinyl group.3. The compound of formula (I) according to claim 2, wherein R1represents an unsubstituted 4-pyridinyl ring or a 4-pyrimidinyl ring; R2represents a phenyl group or a naphthalene ring, the phenyl group andthe naphthalene ring being optionally substituted by 1 to 4 substituentsselected from a C₁₋₃ alkyl group, a halogen atom, a hydroxyl group, aC₁₋₂ alkoxy group, a phenyl group, a pyrrolidine ring, a piperidine ringor an azepine ring; R3 represents a hydrogen atom; R5 represents ahydrogen atom; X represents two hydrogen atoms; Y represents a carbonylgroup or a methylene group optionally substituted by a hydroxyl group;and n, p and q represent 0, 2 and 0, respectively.
 4. The compound offormula (I) according to claim 1, which is selected from the groupconsisting of:1′-[(2S)-2-hydroxy-2-phenyl-ethyl]-8-phenyl-2-(4-pyridinyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;9-(2-oxo-2-phenyl-ethyl)-8-phenyl-2-(4-pyridinyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;9-[2-(3-bromo-phenyl)-2-oxo-ethyl]-8-phenyl-2-(4-pyridinyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;9-[2-(4-chloro-phenyl)-2-oxo-ethyl]-8-phenyl-2-(4-pyridinyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;9-[2-(4-fluoro-phenyl)-2-oxo-ethyl]-8-phenyl-2-(4-pyridinyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;9-[2-(3-fluoro-phenyl)-2-oxo-ethyl]-8-phenyl-2-(4-pyridinyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;9-[2-(4-methoxy-phenyl)-2-oxo-ethyl]-8-phenyl-2-(4-pyridinyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;9-[2-(oxo-2-(4-pyrrolidin-1-yl-phenyl)-ethyl]-8-phenyl-2-(4-pyridinyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;9-(2-biphenyl-4-yl-2-oxo-ethyl)-8-phenyl-2-(4-pyridinyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;9-(2-oxo-2-p-tolyl-ethyl)-8-phenyl-2-(4-pyridinyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;9-(2-naphthalen-2-yl-2-oxo-ethyl)-8-phenyl-2-(4-pyridinyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;9-[2-(3-methoxy-phenyl)-2-oxo-ethyl]-8-phenyl-2-(4-pyridinyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;9-[2-(2-methoxy-phenyl)-2-oxo-ethyl]-8-phenyl-2-(4-pyridinyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;9-[(2S)-2-oxo-2-phenyl-ethyl]-2,8-dipyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;9-[2-(3-bromo-phenyl)-2-oxo-ethyl]-2,8-dipyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;9-(2-hydroxy-2-phenyl-ethyl)-2,8-dipyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;9-[2-(3-bromo-phenyl)-2-hydroxy-ethyl]-2,8-dipyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;9-[2-(3-fluoro-phenyl)-2-oxo-ethyl]-2,8-dipyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;9-[2-hydroxy-2-(4-methoxy-phenyl)-ethyl]-8-phenyl-2-pyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;9-(2-hydroxy-2-p-tolyl-ethyl)-8-phenyl-2-pyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;(−)-9-(2-oxo-2-phenyl-ethyl)-2,8-dipyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;(+)-9-(2-oxo-2-phenyl-ethyl)-2,8-dipyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;9-[2-hydroxy-2-(3-bromo-phenyl)-ethyl]-8-phenyl-2-pyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;9-[2-hydroxy-2-(4-chloro-phenyl)-ethyl]-8-phenyl-2-pyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;9-[2-(3-fluoro-phenyl)-2-hydroxy-ethyl]-2,8-dipyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;9-[2-hydroxy-2-(4-fluoro-phenyl)-ethyl]-8-phenyl-2-pyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;9-[2-hydroxy-2-(4-phenyl-phenyl)-ethyl]-8-phenyl-2-pyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;and9-[2-hydroxy-2-naphthalen-2-yl-ethyl]-8-phenyl-2-pyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;or a salt thereof.
 5. A compound of formula (III)

wherein p+q=0-3; R1 represents a 2, 3 or 4-pyridine ring or a 2, 4 or5-pyrimidine ring, the rings being optionally substituted by a C₁₋₄alkyl group, a C₁₋₄ alkoxy group or a halogen atom; R3 represents ahydrogen atom or a C₁₋₆ alkyl group; R4 represents a phenyl group, anaphthalene ring or a pyridinyl group, the groups and the ring beingoptionally substituted by 1 to 4 substituents selected from a C₁₋₆ alkylgroup, a methylenedioxy group, a halogen atom, a C₁₋₂ perhalogenatedalkyl group, a C₁₋₃ halogenated alkyl group, a hydroxyl group, a C₁₋₄alkoxy group, a nitro, a cyano, an amino, a C₁₋₅ monoalkylamino group ora C₂₋₁₀ dialkylamino group; and R5 represents a hydrogen atom, a C₁₋₆alkyl group or a halogen atom.
 6. A pharmaceutical compositioncomprising a compound of formula (I) or a pharmaceutically acceptablesalt thereof, or a solvate thereof, according to claim 1 in combinationwith one or more pharmaceutically acceptable diluent, excipient or acarrier.
 7. The pharmaceutical composition according to claim 6, whereinthe compound of formula (I) is selected from the group consisting of:1′-[(2S)-2-hydroxy-2-phenyl-ethyl]-8-phenyl-2-(4-pyridinyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;9-(2-oxo-2-phenyl-ethyl)-8-phenyl-2-(4-pyridinyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;9-[2-(3-bromo-phenyl)-2-oxo-ethyl]-8-phenyl-2-(4-pyridinyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;9-[2-(4-chloro-phenyl)-2-oxo-ethyl]-8-phenyl-2-(4-pyridinyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;9-[2-(4-fluoro-phenyl)-2-oxo-ethyl]-8-phenyl-2-(4-pyridinyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;9-[2-(3-fluoro-phenyl)-2-oxo-ethyl]-8-phenyl-2-(4-pyridinyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;9-[2-(4-methoxy-phenyl)-2-oxo-ethyl]-8-phenyl-2-(4-pyridinyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;9-[2-(oxo-2-(4-pyrrolidin-1-yl-phenyl)-ethyl]-8-phenyl-2-(4-pyridinyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;9-(2-biphenyl-4-yl-2-oxo-ethyl)-8-phenyl-2-(4-pyridinyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;9-(2-oxo-2-p-tolyl-ethyl)-8-phenyl-2-(4-pyridinyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;9-(2-naphthalen-2-yl-2-oxo-ethyl)-8-phenyl-2-(4-pyridinyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;9-[2-(3-methoxy-phenyl)-2-oxo-ethyl]-8-phenyl-2-(4-pyridinyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;9-[2-(2-methoxy-phenyl)-2-oxo-ethyl]-8-phenyl-2-(4-pyridinyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;9-[(2S)-2-oxo-2-phenyl-ethyl]-2,8-dipyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;9-[2-(3-bromo-phenyl)-2-oxo-ethyl]-2,8-dipyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;9-(2-hydroxy-2-phenyl-ethyl)-2,8-dipyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;9-[2-(3-bromo-phenyl)-2-hydroxy-ethyl]-2,8-dipyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;9-[2-(3-fluoro-phenyl)-2-oxo-ethyl]-2,8-dipyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;9-[2-hydroxy-2-(4-methoxy-phenyl)-ethyl]-8-phenyl-2-pyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;9-(2-hydroxy-2-p-tolyl-ethyl)-8-phenyl-2-pyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;(−)-9-(2-oxo-2-phenyl-ethyl)-2,8-dipyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;(+)-9-(2-oxo-2-phenyl-ethyl)-2,8-dipyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;9-[2-hydroxy-2-(3-bromo-phenyl)-ethyl]-8-phenyl-2-pyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;9-[2-hydroxy-2-(4-chloro-phenyl)-ethyl]-8-phenyl-2-pyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;9-[2-(3-fluoro-phenyl)-2-hydroxy-ethyl]-2,8-dipyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;9-[2-hydroxy-2-(4-fluoro-phenyl)-ethyl]-8-phenyl-2-pyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;9-[2-hydroxy-2-(4-phenyl-phenyl)-ethyl]-8-phenyl-2-pyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;9-[2-hydroxy-2-naphthalen-2-yl-ethyl]-8-phenyl-2-pyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;or a salt thereof.
 8. A method of treating a disease in a patient, saiddisease selected from the group consisting of Alzheimer's disease,Parkinson's disease, taupathies, noninsulin dependent diabetes, obesity,manic depressive illness and schizophrenia, comprising administering tosaid patient a therapeutically effective amount of a compound of formula(I) or a pharmaceutically acceptable salt thereof:

wherein: X represents two hydrogen atoms, a sulfur atom, an oxygen atomor a C₁₋₂ alkyl group and a hydrogen atom; Y represents a bond, acarbonyl group, a methylene group optionally substituted by one or twogroups chosen from a C₁₋₆ alkyl group, a hydroxyl group, a C₁₋₄ alkoxygroup, a C₁₋₂ perhalogenated alkyl group or an amino group; R1represents a 2, 3 or 4-pyridine ring or a 2, 4 or 5-pyrimidine ring, therings being optionally substituted by a C₁₋₄ alkyl group, a C₁₋₄ alkoxygroup or a halogen atom; R2 represents a phenyl group or a naphthalenering; the phenyl group or the naphthalene ring being optionallysubstituted by 1 to 4 substituents selected from a C₁₋₆ alkyl group, amethylenedioxy group, a halogen atom, a C₁₋₂ perhalogenated alkyl group,a C₁₋₃ halogenated alkyl group, a hydroxyl group, a C₁₋₄ alkoxy group, anitro, a cyano, an amino, a C₁₋₅ monoalkylamino group, a C₂₋₁₀dialkylamino group, a phenyl group, a pyrrolidine ring, a piperidinering or an azepine ring; R3 represents a hydrogen atom or a C₁₋₆ alkylgroup; R4 represents a phenyl group, a naphthalene ring or a pyridinylgroup, the groups and the ring being optionally substituted by 1 to 4substituents selected from a C₁₋₆ alkyl group, a methylenedioxy group, ahalogen atom, a C₁₋₂ perhalogenated alkyl group, a C₁₋₃ halogenatedalkyl group, a hydroxyl group, a C₁₋₄ alkoxy group, a nitro, a cyano, anamino, a C₁₋₅ monoalkylamino group or a C₂₋₁₀ dialkylamino group; R5represents a hydrogen atom, a C₁₋₆ alkyl group or a halogen atom; nrepresents 0 to 3; and p+q=0-3.
 9. The method according to claim 8,wherein R4 represents a phenyl group or a pyridinyl group.
 10. Themethod according to claim 9, wherein R1 represents an unsubstituted4-pyridinyl ring or a 4-pyrimidinyl ring; R2 represents a phenyl groupor a naphthalene ring, the phenyl group and the naphthalene ring beingoptionally substituted by 1 to 4 substituents selected from a C₁₋₃ alkylgroup, a halogen atom, a hydroxyl group, a C₁₋₂ alkoxy group, a phenylgroup, a pyrrolidine ring, a piperidine ring or an azepine ring; R3represents a hydrogen atom; R5 represents a hydrogen atom; X representstwo hydrogen atoms; Y represents a carbonyl group or a methylene groupoptionally substituted by a hydroxyl group; and n, p and q represent 0,2 and 0, respectively.
 11. The method according to claim 8, wherein thecompound of formula (I) is selected from the group consisting of:1′-[(2S)-2-hydroxy-2-phenyl-ethyl]-8-phenyl-2-(4-pyridinyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;9-(2-oxo-2-phenyl-ethyl)-8-phenyl-2-(4-pyridinyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;9-[2-(3-bromo-phenyl)-2-oxo-ethyl]-8-phenyl-2-(4-pyridinyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;9-[2-(4-chloro-phenyl)-2-oxo-ethyl]-8-phenyl-2-(4-pyridinyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;9-[2-(4-fluoro-phenyl)-2-oxo-ethyl]-8-phenyl-2-(4-pyridinyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;9-[2-(3-fluoro-phenyl)-2-oxo-ethyl]-8-phenyl-2-(4-pyridinyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;9-[2-(4-methoxy-phenyl)-2-oxo-ethyl]-8-phenyl-2-(4-pyridinyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;9-[2-(oxo-2-(4-pyrrolidin-1-yl-phenyl)-ethyl]-8-phenyl-2-(4-pyridinyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;9-(2-biphenyl-4-yl-2-oxo-ethyl)-8-phenyl-2-(4-pyridinyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;9-(2-oxo-2-p-tolyl-ethyl)-8-phenyl-2-(4-pyridinyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;9-(2-naphthalen-2-yl-2-oxo-ethyl)-8-phenyl-2-(4-pyridinyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;9-[2-(3-methoxy-phenyl)-2-oxo-ethyl]-8-phenyl-2-(4-pyridinyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;9-[2-(2-methoxy-phenyl)-2-oxo-ethyl]-8-phenyl-2-(4-pyridinyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;9-[(2S)-2-oxo-2-phenyl-ethyl]-2,8-dipyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;9-[2-(3-bromo-phenyl)-2-oxo-ethyl]-2,8-dipyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;9-(2-hydroxy-2-phenyl-ethyl)-2,8-dipyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;9-[2-(3-bromo-phenyl)-2-hydroxy-ethyl]-2,8-dipyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;9-[2-(3-fluoro-phenyl)-2-oxo-ethyl]-2,8dipyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;9-[2-hydroxy-2-(4-methoxy-phenyl)-ethyl]-8-phenyl-2-pyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;9-(2-hydroxy-2-p-tolyl-ethyl)-8-phenyl-2-pyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;(−)-9-(2-oxo-2-phenyl-ethyl)-2,8-dipyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;(+)-9-(2-oxo-2-phenyl-ethyl)-2,8-dipyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;9-[2-hydroxy-2-(3-bromo-phenyl)-ethyl]-8-phenyl-2-pyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;9-[2-hydroxy-2-(4-chloro-phenyl)-ethyl]-8-phenyl-2-pyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;9-[2-(3-fluoro-phenyl)-2-hydroxy-ethyl]-2,8-dipyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;9-[2-hydroxy-2-(4-fluoro-phenyl)-ethyl]-8-phenyl-2-pyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;9-[2-hydroxy-2-(4-phenyl-phenyl)-ethyl]-8-phenyl-2-pyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;and9-[2-hydroxy-2-naphthalen-2-yl-ethyl]-8-phenyl-2-pyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one;or a salt thereof.
 12. The method according to claim 8, wherein thedisease is selected from the group consisting of Alheimer's disease,Parkinson's disease and taupathies.
 13. The method according to claim12, wherein the disease is Alzheimer's disease.
 14. The method accordingto claim 12, wherein the disease is Parkinson's disease.
 15. The methodaccording to claim 12, wherein the disease is taupathies.
 16. The methodaccording to claim 8, wherein the disease is selected from the groupconsisting of non-insulin dependent diabetes; obesity; manic depressiveillness; and schizophrenia.
 17. The method according to claim 16,wherein the disease is non-insulin dependent diabetes.